Treatment of neurotic disorders

ABSTRACT

Use of escitalopram (the S-(+)-enantiomer of citalopram) or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful in the treatment of neurotic disorders is provided, including anxiety states, in particular generalised anxiety disorder and social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder and panic attacks.

FIELD OF INVENTION

[0001] The present invention relates to the use of the compoundescitalopram (INN-name), which is the S-enantiomer of the well-knownantidepressant drug citalopram, i.e.(S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,or a pharmaceutically acceptable salt thereof for the preparation ofmedicaments for the treatment of neurotic disorders, including anxietystates and panic attacks.

BACKGROUND OF THE INVENTION

[0002] Citalopram is a well-known antidepressant drug that has now beenon the market for some years and has the following structure:

[0003] It is a selective, centrally acting serotonin(5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly havingantidepressant activities. The antidepressant activity of the compoundhas been reported in several publications, eg. J. Hyttel, Prog.Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A.Gravem, Acta Psychiatr. Scand, 1987, 75, 478-486, and it is now marketedfor the treatment of depression and panic disorders. The compound hasfurther been disclosed to show effects in the treatment of dementia andcerebrovascular disorders, EP-A 474580.

[0004] Escitolopram and a method for its preparation are disclosed inU.S. Pat. No. 4,943,590. The stereo selectivity of citalopram, i.e. the5-HT-reuptake inhibition in the S-enantiomer, and accordingly, theantidepressant effect of said enantiomer is also disclosed. S-citalopramis now in development as an antidepressant.

[0005] Studies have shown that patients suffering from neuroticdisorders including anxiety disorders, especially generalised anxiety,and panic attacks, in particular in association with agoraphobia, have aquality of life impairment comparable with or greater than thedisability found in patients with alcoholism, schizophrenia orpersonality disorders. Furthermore, current treatments are not alwayseffective or cause unacceptable side effects.

[0006] Consequently, there is a need for alternative therapies useful inthe treatment of neurotic disorders.

[0007] Escitalopram has now been found to show potent effects in modelsof neurotic disorders such as anxiolytic effect and prominent effect inthe treatment of panic attacks and obsessive compulsive disorder.

DESCRIPTION OF THE INVENTION

[0008] According to the present invention, a novel use of escitalopram,namely for the preparation of a medicament useful in the treatment ofneurotic disorders is provided.

[0009] Throughout this specification and claims the term neuroticdisorders is used to designate a group of mental disorders, includinganxiety states, in particular generalised anxiety disorder and socialanxiety disorder, post traumatic stress disorder, obsessive compulsivedisorder and panic attacks.

[0010] The terms generalised anxiety disorder, social anxiety disorder,post traumatic stress disorder and obsessive compulsive disorder are asdefined in DSM IV.

[0011] The phrase “panic attacks” contemplates treatment of any disease,which is associated with panic attacks including panic disorder,specific phobias, social phobia and agoraphobia in which panic attacksoccur. These disorders are further defined in the DSM IV. A panic attackis a discrete period in which there is a sudden onset of intenseapprehension, fearfulness or terror, often associated with feelings ofimpending doom. During the attack, symptoms such as palpitations,sweating, trembling, sensations of shortness of breath, feeling ofchoking, chest pain or discomfort, nausea, feeling dizzy, feelings ofunreality, fear of losing control or going crazy, fear of dying,paresthesias and chills or hot flushes are present.

[0012] Panic disorders are characterised by recurrent unexpected panicattacks about which there is a persistent concern. Agoraphobia isanxiety about, or avoidance of, places or situations from which escapemight be difficult or in which help may not be available in the event ofa panic attack. Specific phobia and social phobia (together formerlysimple phobia) are characterised by marked and persistent fear that isexcessive or unreasonable, cued by the presence or anticipation of aspecific object or situation (flying, heights, animals, seeing bloodetc.) or social performance situations.

[0013] The disorders in which panic attacks occur are differentiatedfrom each other by the predictability of the occurrence of the attacks,for example, in panic disorder the attacks are unpredictable and notassociated with any particular event, whereas in specific phobia theattacks are triggered by specific stimuli.

[0014] The phrase “treatment of panic disorder” means a reduction in thenumber or prevention of attacks and/or relief of the severity of theattacks. Similarly, the treatment of generalised anxiety disorder,social anxiety disorder, post traumatic stress disorder and obsessivecompulsive disorder include the treatment or prevention of thesediseases, or the relief of the symptoms thereof.

[0015] According to the invention, escitalopram may be used as the baseof the compound or as a pharmaceutically acceptable acid addition saltthereof or as an anhydrate or hydrate of such salt. The salts of thecompound used in the invention are salts formed with non-toxic organicor inorganic acids, in particular the oxalate.

[0016] Escitalopram has been found to show prominent effects differentfrom the effects of the racemate in the “Inhibition of footshock-inducedultrasonic vocalisation in adult rats”- test, the “Mice Black and WhiteTest” setup, and in the polydipsia test. These models are standardanimal models for anxiolytic effect and effect on panic attacks and forobsessive compulsive disorder, respectively.

[0017] According to the invention, escitalopram or a pharmaceuticallyacceptable salt thereof may be administered in any suitable way e.g.orally or parenterally, and it may be presented in any suitable form forsuch administration, e.g. in the form of tablets, capsules, powders,syrups or solutions or dispersions for injection. Preferably, and inaccordance with the purpose of the present invention, the compound ofthe invention is administered in the form of a solid pharmaceuticalentity, suitably as a tablet or a capsule or in the form of asuspension, solution or dispersion for injection.

[0018] Methods for the preparation of solid pharmaceutical preparationsare well known in the art. Tablets may thus be prepared by mixing theactive ingredients with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a convenient tabletting machine.Examples of adjuvants or diluents comprise: corn starch, lactose,talcum, magnesium stearate, gelatine, lactose, gums, and the like. Anyother adjuvant or additive such as colourings, flavourings,preservatives, etc. may also be used provided that they are compatiblewith the active ingredients.

[0019] The compound of the invention is most conveniently administeredorally in unit dosage forms such as tablets or capsules, containing theactive ingredient in a dose from about 1.0 mg to 50 mg, preferably 5mg/day to 40 mg/day, most preferably 10 mg/day to 20 mg/day.

[0020] The oxalate of escitalopram may be prepared as described in U.S.Pat. No. 4,943,590 and the base and other pharmaceutically acceptablesalts may be obtained therefrom by standard procedures.

[0021] Thus the acid addition salts used according to the invention maybe obtained by treatment of escitalopram with the acid in an inertsolvent followed by precipitation, isolation and optionallyre-crystallisation by known methods and if desired micronisation of thecrystalline product by wet or dry milling or another convenient process,or preparation of particles from a solvent-emulsification process.

[0022] Pharmacological Tests

[0023] Escitalopram was tested in well recognised and reliable testmodels of effects on neurotic disorders. Citalopram-racemate wasincluded for comparison purposes.

[0024] The Footshock-Induced Vocalisation Test in Adult Rats

[0025] The footshock-induced vocalisation test in adult rats (describedin detail in Sánchez C., Effect of serotonergic drugs onfootshock-induced ultrasonic vocalization in adult male rats. Behav.Pharmacol. 1993; 4:267-277) is a test for anxiolytic and anti-paniceffects.

[0026] Experimental Procedure

[0027] Male rats (Wistar W U, Charles River, Germany), weighing 150-175g at the beginning of the study were used.

[0028] Briefly, test cages (22 cm×22 cm×22 cm) made of grey Perspex andequipped with a metal grid floor were used. Footshocks were deliveredfrom a two pole shocker and a microphone sensitive to ultrasounds in therange of 20-30 kHz was placed in the centre of the lid of the test cage.The ultrasounds were sent from the microphone to a preamplifier andconverted from AC signals to DC signals in a signal rectifier. Theaccumulated time, in which the voltage of the rectified signal waslarger than the voltage of a previously determined treshold level, wasrecorded

[0029] Twenty-four hours before the first test session the animals wereprimed. A rat was placed in each test cage and received, immediatelythereafter, four 1.0 mA inescapable footshocks each of a duration of 10sec and with an intershock interval of 5 sec. The animals were left inthe test cage for 6 min after the last shock. On test days, drug orsaline was given 30 min before test. The rats received four 1.0 mAinescapable footshocks each of a duration of 10 sec. The intershockinterval was 5 sec. Recording of ultrasonic vocalisation started 1 mlafter the last shock and lasted for 5 min. The total time spent onvocalisation was recorded. After a wash-out period of one week the ratswere used in a new test session. The rats were used for a total of 7-8weeks. At each test session, the animal groups were randomly allocatedto treatment with saline or test drug. Each treatment group consisted of8 animals, one saline and 2-4 drug treated groups were included at eachsession. Each drug was tested at least in two separate experiments withoverlapping doses.

[0030] Results

[0031] The experiments showed that the maximum effect was 60-70%inhibition for citalopram-racemate whereas escitalopram was able toinhibit vocalisation completely.

[0032] Black and white Box Test

[0033] This is a test for anxiolytic effects. The test model is furtherdescribed in Sánchez, C. (1995) Pharmacol. Toxicol. 77, 71-78.

[0034] Test Procedure

[0035] Male mice (Lundbeck strain, Charles River, Germany) weighing30-35 g were housed in groups of 4 in macrolon cages type II under areversed 12 h day/night cycle (lights off 7 p.m.). The mice were adaptedto the reversed light/dark cycle for at least 3 weeks prior to testing.The room temperature (21±2° C.), relative humidity (55±5%), and airexchange (16 times per h) were automatically controlled. The animals hadfree access to commercial food pellets and water.

[0036] The test box used was designed as described by Sanchez (1995)(supra). Briefly, the test box (45 cm×27 cm×27 cm) was open-topped anddivided into two compartments (ratio 2:3) by a partition which was blackon the side facing the black compartment and white on the side facingthe white compartment The smaller chamber was made of black perspex. Thelarger chamber was made of white perspex except for the lowest 7.5 cm.This part was made of transparent perspex (outer walls) and blackperspex (partition). The white compartment was connected to the blackcompartment by a 7.5 cm×7.5 cm opening in the partition. The floor ofthe white compartment was divided into 9 fields, and the floor of theblack was divided into 6 fields. The white compartment was illuminatedby means of a Schott KL 1500 electronic lamp emitting cold lightcorresponding to a light intensity of 560 Lux. The mouse test-system wasfully automated by 2 rows of 11 infrared light sources and photocells inthe transverse direction and 1 row of 16 in the longitudinal direction(lower row). The lower row of photocells (2 cm above cage floor)detected horizontal locomotor activity (crossing, entries, and time ineach compartment), whereas the upper row of photocells (5 cm above cagefloor) detected rearing activity. The accumulated data for 1 minintervals were recorded from 4 test boxed simultaneously and stored in aParadox data base.

[0037] The test boxes were placed in a dark and quiet room. The micewere transported to the test room in a darkened container about 2 hbefore test. The test room was separated into two parts by a blackcurtain. The drug treatment took place in one part of the room using aminimum of red light. After dosing, the mice were placed individually inmacrolon type II cages until test. The pretreatment time was 30 min. Thetest boxes were placed in the other part of the room. The test wasstarted by placing the mouse in the centre of the brightly-lit whitecompartment facing the opening to the black compartment. The testduration was 5 min and the number of rears and line crossings betweensquares in both the black and the white compartment, number of entriesinto the black compartment and time spent in the white compartment wereassessed.

[0038] Results

[0039] Escitalopram showed prominent effects in this model.

[0040] Schedule-Induced Polydipsia

[0041] Food deprived rats exposed to a procedure in which food isdelivered intermittently will drink large amounts of water if given theopportunity to do so. This behavioural phenomenon is calledschedule-induced polydipsia and can be considered as an excessiveexpression of a normal behaviour. Schedule-induced polydipsia isregarded as a model of obsessive-compulsive disorder (Woods et al.1993).

[0042] Test Procedure:

[0043] Male wistar rats (Møllegård) housed in pairs and kept on afood-restricted diet (80% of normal body weight) for 2 weeks before thestart of testing and throughout the duration of testing. To inducepolydipsia rats were placed in test chambers where a pellet dispenserautomatically dispensed one 60 mg food pellet every 60 seconds. Waterwas available at all times in the test chamber. Rats were tested 4-5times per week, after 3-4 weeks training 70% of the rats weredrinking>10 ml per 30 min test session.

[0044] Once the rats had attained a steady drinking level compoundscould be tested. Citalopram (40 mg/kg) or Lu 26-054 (20 mg/kg) wereadministered orally 60 min prior to testing and at 10:00 on the non-testdays. The water intake was presented as a percentage of the pre-dosing(baseline) level.

[0045] Results:

[0046] Escitalopram produced a significant reduction in water intake,whereas citalopram was without effect.

[0047] All these studies show that escitalopram has potent anti neuroticdiseases effects, in particular anxiolytic effects and effects on panicattacks and obsessive compulsive disorder.

What is claimed is:
 1. A method of treating a neurotic disorder, saidmethod comprising administration of a pharmaceutically effective amountof escitalopram or a pharmaceutically acceptable salt thereof to apatient in need thereof.
 2. The method of claim 1, wherein thepharmaceutically effective amount of escitalopram or a pharmaceuticallyacceptable salt thereof is in a unit dose form.
 3. The method of claim2, wherein the unit dose contains 1.0 to 50 mg/day of escitalopram or apharmaceutically acceptable salt thereof.
 4. The method of claim 2,wherein the unit dose contains 5 to 40 mg/day of escitalopram or apharmaceutically acceptable salt thereof.
 5. The method of claim 2,wherein the unit dose contains 10 to 20 mg/day of escitalopram or apharmaceutically acceptable salt thereof.
 6. The method of claim 1,wherein said neurotic disorder is generalized anxiety disorder.
 7. Themethod of claim 1, wherein said neurotic disorder is social anxietydisorder.
 8. The method of claim 1, wherein said neurotic disorder ispost traumatic stress disorder.
 9. The method of claim 1, wherein saidneurotic disorder is obsessive compulsive disorder.
 10. The method ofclaim 1, wherein said neurotic disorder is panic attacks.
 11. The methodof claim 1, wherein said neurotic disorder is panic disorder.
 12. Themethod of claim 1, wherein said neurotic disorder is specific phobias.13. The method of claim 1, wherein said neurotic disorder is socialphobia.
 14. The method of claim 1, wherein said neurotic disorder isagoraphobia.